Reactions of 1,2-diaza-1,3-dienes with thiol derivatives: a versatile construction of nitrogen/sulfur containing heterocycles Orazio A. Attanasi a, * , Paolino Filippone a , Samuele Lillini a , Fabio Mantellini a , Simona Nicolini a , Jesu ´ s M. de los Santos b , Roberto Ignacio b , Domitila Aparicio b , Francisco Palacios b, * a Istituto di Chimica Organica, Universita ` degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti, 24, 61029 Urbino (PU), Italy b Departamento de Quı ´mica Orga ´nica I, Facultad de Farmacia, Universidad del Paı ´s Vasco, Apartado 450, 01080 Vitoria, Spain article info Article history: Received 5 May 2008 Received in revised form 18 June 2008 Accepted 10 July 2008 Available online 15 July 2008 abstract The synthesis of substituted 2,3-dihydro-1,4-thiazines, fused cycloalkyl-1,4-thiazines,1,4-benzothiazines and fused cycloalkyl-1,4-benzothiazines by 1,4-addition of 1,2-aminothiols to 1,2-diaza-1,3-dienes bearing carboxylate, carboxamide, or phosphorylated groups and subsequent internal heterocyclization is described. The reaction of carboxylated 1,2-diaza-1,3-butadienes with 2-(butylamino)ethanethiol af- fords 1,4-thiazinan-3-ones. The solid-phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-aminothiols produces 2,3-dihydro-1,4-thiazines and 1,4-benzothiazines. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Nitrogen-containing heterocycles are undoubtedly one of the most important targets in organic chemistry. They are widely dis- tributed in natural products and in pharmaceutical agents, and numerous studies for their chemistry and synthesis have been reported. 1 Consequently new reactions, in which nitrogen-con- taining heterocycles can be prepared in a chemo- and stereo- selective way, will be broadly applicable for endeavours in natural product synthesis and medicinal chemistry. The 1,4-thiazine ring system is important in organic chemistry because it constitutes the skeleton of natural products such as the two cytotoxic terpene quinones, conicaquinones A and B, 2a xanthiazone 2b and xanthisi- de, 2c and it is known to play an important role in pigments and dyestuffs. 3 In addition, 1,4-thiazine derivatives also exhibit poten- tial biological activities. Among these, 1,4-thiazine-3-carboxylic acid derivatives are well known for their antibacterial activity, 4a aroyldihydro-1,4-thiazines are effective antiinflammatories, 4b and some bicyclic thiazines are attracting the increasing interest in medicinal chemistry due to their hepatoprotective, 4c calcium antagonistic, 4d vasopressin receptor antagonistic 4e and anticancer activities. 4f,g Similarly, there is a wide precedence documenting the potential of their benzo derivatives, 1,4-benzothiazines and their analogues, for biological and therapeutic activity. For example, these compounds were reported as calcium channel blockers, 5a–c Na/H exchange inhibitors, 5d antifungal, 5e,f antibacterial, 5f anti- microbial 5g and antihypertensive 5h,i agents, to name just a few. Furthermore, it is known that the presence of phosphorus sub- stituents could regulate important biological functions, 6 and the introduction of organophosphorus functionalities in simple synthons may afford useful substrates for the preparation of biologically active compounds. In this context, carboxylated 1,2- diaza-1,3-butadienes 7 have been widely used for the preparation of heterocyclic compounds, 8 while phosphorylated 1,2-diaza-1,3- butadienes have been used for the preparation of a-amino- phosphonates, 9 pyridazines, 10 pyrazines and quinoxalines. 8d As part of our ongoing research programs on the preparation of three, 11 five 12 and six 13 membered nitrogen-containing heterocy- cles, as well as the synthesis of new amino phosphorus de- rivatives, 9,14 here we report the behaviour of thiol derivatives I towards 1,2-diaza-1,3-dienes II. The obtained hydrazones III pro- vide flexible access to different classes of nitrogen/sulfur containing heterocycles by means of controlled regioselective cyclizations (Chart 1). The presence of different functional groups in many po- sitions of these heterocycles merits especial emphasis since such compounds are, in turn, potential starting materials for further interesting structural modifications, making them suitable for more complex heterocyclic systems. In this work, we also investigated the use of polymer-bound 1,2- diaza-1,3-butadienes as building blocks for the facile solid-phase preparation of thiazine and benzothiazine derivatives. 2. Results and discussion 4-Phosphinyl and 4-phosphonyl-1,2-diaza-1,3-butadienes 15 1a,b (R 1 ¼P(O)Ph 2 , P(O)(OEt) 2 ;R 2 ¼OEt), easily reacted with 2- mercaptoethylamine hydrochloride 2a (R 3 ¼H, Y¼NH 3 Cl) in * Corresponding authors. E-mail address: orazio.attanasi@uniurb.it (O.A. Attanasi). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.07.030 Tetrahedron 64 (2008) 9264–9274